Isopropyl 2-ethoxyacetate—an efficient acylating agent for lipase-catalyzed kinetic resolution of amines in batch and continuous-flow modes

Abstract

Productivity [conversion (c) and specific reaction rate (rbatch or rflow)] and enantiomer selectivity [enantiomeric ratio (E) and enantiomeric excess (ee) of the products] of ethyl and isopropyl esters of acetic, 2-methoxyacetic and 2-ethoxyacetic acids as acylating agents were compared in the N-acylation of (±)-1-phenylethanamine rac-1 catalyzed by variously immobilized forms of Candida antarctica lipase B (CaLB) using shake flasks and continuous-flow reactors. The effect of the temperature in the 0–80 °C range on productivity and enantiomer selectivity in KRs of rac-1 was investigated with the isopropyl esters in continuous-flow mode using CaLB-filled minireactors. Isopropyl 2-ethoxyacetate surpassed the performance of ethyl 2-methoxyacetate in terms of both productivity (1.9–2.9 times higher rate in batch mode) and enantiomeric selectivity (ee(R)-amide>99.9% compared to 99.8%) providing at 40 °C high volumetric productivity (2.22 kg L−1 h−1), specific reaction rate and enantiomeric excess (rflow=783 μmol min−1 g−1, ee(R)-2c>99.9%).